PL195164B1 - Diastereomer salts of (±)-alpha-(difluoromethyl)ornithine-monohydrochloride monohydrate and method of separation of (+)- alpha-(difluoromethyl)ornithine - Google Patents
Diastereomer salts of (±)-alpha-(difluoromethyl)ornithine-monohydrochloride monohydrate and method of separation of (+)- alpha-(difluoromethyl)ornithineInfo
- Publication number
- PL195164B1 PL195164B1 PL99346900A PL34690099A PL195164B1 PL 195164 B1 PL195164 B1 PL 195164B1 PL 99346900 A PL99346900 A PL 99346900A PL 34690099 A PL34690099 A PL 34690099A PL 195164 B1 PL195164 B1 PL 195164B1
- Authority
- PL
- Poland
- Prior art keywords
- ornithine
- difluoromethyl
- alpha
- toluoyl
- tartaric acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 150000003839 salts Chemical class 0.000 title claims description 10
- 238000000926 separation method Methods 0.000 title claims description 8
- VLCYCQAOQCDTCN-ZCFIWIBFSA-N α-difluoromethylornithine Chemical compound NCCC[C@@](N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-ZCFIWIBFSA-N 0.000 title description 2
- FJPAMFNRCFEGSD-QYCVXMPOSA-N (2s)-2,5-diamino-2-(difluoromethyl)pentanoic acid;hydrate;hydrochloride Chemical class O.Cl.NCCC[C@@](N)(C(F)F)C(O)=O FJPAMFNRCFEGSD-QYCVXMPOSA-N 0.000 title 1
- -1 (-)-O Chemical class 0.000 claims abstract description 12
- CMIBUZBMZCBCAT-HZPDHXFCSA-N (2r,3r)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HZPDHXFCSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 15
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 15
- 229960003104 ornithine Drugs 0.000 claims description 15
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 14
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003495 polar organic solvent Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 230000020477 pH reduction Effects 0.000 claims description 3
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 102000052812 Ornithine decarboxylases Human genes 0.000 abstract 1
- 108700005126 Ornithine decarboxylases Proteins 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- ODAOACQIMPICSJ-FHNDMYTFSA-N (2S)-2,5-diaminopentanoic acid hydrate hydrochloride Chemical compound O.Cl.NCCC[C@H](N)C(O)=O ODAOACQIMPICSJ-FHNDMYTFSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229940122060 Ornithine decarboxylase inhibitor Drugs 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002818 ornithine decarboxylase inhibitor Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Opis wynalazkuDescription of the invention
Obecny wynalazek dotyczy diastereomerycznych soli (+)- lub (-)-a-(difluorometylo)ornityny oraz sposobu rozdziału (±)-a-(difluorometylo)ornityny, korzystnie z wytworzeniem jednowodzianu jednochlorowodorku (-)-a-(Difluorometylo)ornityny. (±)-a-(difluorometylo)ornityna jest inhibitorem dekarboksylazy ornityny i przejawia różnorodne działanie farmakologiczne (US-A-4,413,141).The present invention relates to diastereomeric salts of (+) - or (-) -? - (difluoromethyl) ornithine and a method of separating (±) - - (difluoromethyl) ornithine, preferably to form (-) -? - (Difluoromethyl) ornithine monohydrate monohydrate. (±) - (difluoromethyl) ornithine is an ornithine decarboxylase inhibitor and has various pharmacological effects (US-A-4,413,141).
Wiadomym jest, że farmakologiczna aktywność (-)-izomeru jest znacząco większa niż aktywność racematu (WO-A-98/25603).It is known that the pharmacological activity of the (-) - isomer is significantly greater than that of the racemate (WO-A-98/25603).
Znane sposoby wytwarzania (-)-izomeru są jednakże pracochłonne i niezadowalające pod względem możliwej do osiągnięcia wydajności i czystości optycznej.The known (-) - isomer production processes are, however, laborious and unsatisfactory in terms of achievable yield and optical purity.
Zgodnie z opisem patentowym Stanów Zjednoczonych Ameryki nr 4,413,141 lub 4,309,442 do rozdziału wykorzystuje się DL-3-amino-3-difluorometylo-2-piperydon o wzorze 2, który najpierw należy wytworzyć z racemicznego jednowodzianu jednochlorowodorku DL-a-(difluorometylo)ornityny na drodze wytworzenia estru metylowego i cyklizacji przy użyciu alkoholanu. Rozdział piperydonu opisano wskazując klasyczne środki rozdzielające takie, jak przykładowo, użycie kwasu (+)-kamforo-10-sulfonowego lub użycie kwasu (+)- lub (-)-binaftylofosforowego.According to U.S. Pat. No. 4,413,141 or 4,309,442, DL-3-amino-3-difluoromethyl-2-piperidone of formula 2 is used for separation, which must first be prepared from racemic DL-α- (difluoromethyl) ornithine monohydrate monohydrate by methyl ester formation and cyclization using an alkoxide. The separation of piperidone is described with reference to classical resolving agents such as, for example, the use of (+) - camphor-10-sulfonic acid or the use of (+) - or (-) - binaphthylphosphoric acid.
Celem obecnego wynalazku jest zapewnienie dostępu do pożądanego izomeru, sposobem prostszym i udoskonalonym pod względem wydajności i uzyskiwanej czystości optycznej.The object of the present invention is to provide the desired isomer with a simpler and improved method in terms of yield and optical purity obtained.
Stwierdzono, że (±)-a-(difluorometylo)ornitynę można rozdzielić stosując dostępny handlowo kwas (-)-O,O'-di-p-toluoilo-L-winowy, unikając okrężnych dróg i eliminując niekorzystne cechy znanego rozwiązania, a w konsekwencji, że można zrealizować postawiony cel w nieoczekiwanie prosty sposób.It has been found that (±) -a- (difluoromethyl) ornithine can be separated using commercially available (-) - O, O'-di-p-toluoyl-L-tartaric acid, avoiding the roundabout paths and eliminating the disadvantages of the known solution and consequently that you can achieve your goal in an unexpectedly simple way.
Obecny wynalazek dotyczy zatem diastereomerycznych soli (+)- lub (-)-a-(difluorometylo)ornityny o wzorze 1 z kwasem (-)-O,O'-di-p-toluoilo-L-winowym, korzystnie 1:1 diastereomerycznej soli (+)- lub (-)-a-(difluorometylo)ornityny z kwasem (-)-O,O'-di-p-toluoilo-L-winowym, a korzystniej 1:1 diastereomerycznej soli (-)-a-(difluorometylo)ornityny z kwasem (-)-O,O'-di-p-toluoilo-L-winowym.The present invention therefore relates to diastereomeric (+) - or (-) - α- (difluoromethyl) ornithine salts of formula I with (-) - O, O'-di-p-toluoyl-L-tartaric acid, preferably 1: 1 diastereomeric (+) - or (-) - a- (difluoromethyl) ornithine salt with (-) - O, O'-di-p-toluoyl-L-tartaric acid, and more preferably 1: 1 diastereomeric salt of (-) - a- (difluoromethyl) ornithine with (-) - O, O'-di-p-toluoyl-L-tartaric acid.
Przy korzystnym stosunku molowym 1:1 czynnika rozdzielającego do (-)-a-(difluorometylo)ornityny, zasadniczo do związania dostępne są dwie wolne grupy aminowe. Zasadniczo oba diastereomery objęte są obecnym wynalazkiem.With the preferred 1: 1 molar ratio of the resolving agent to (-) -? - (difluoromethyl) ornithine, essentially two free amino groups are available for binding. Essentially both diastereomers are included in the present invention.
Dalszym przedmiotem obecnego wynalazku jest sposób rozdziału (±)-a-(difluorometylo)ornityny, który zgodnie z wynalazkiem prowadzi się stosując kwas (-)-O,O'-di-p-toluoilo-L-winowy.The present invention further relates to a process for the separation of (±) - (difluoromethyl) ornithine, which according to the invention is carried out using (-) - O, O'-di-p-toluoyl-L-tartaric acid.
Rozdział (±)-a-(difluorometylo)ornityny przy użyciu kwasu (-)-O,O'-di-p-toluoilo-L-winowego dogodnie prowadzi się w obecności mieszaniny wody i mieszającego się z wodą polarnego rozpuszczalnika organicznego.The separation of (±) - (difluoromethyl) ornithine with (-) - O, O'-di-p-toluoyl-L-tartaric acid is conveniently carried out in the presence of a mixture of water and a water-miscible polar organic solvent.
Odpowiednimi mieszającymi się z wodą polarnymi rozpuszczalnikami organicznymi są, przykładowo, niższe alkohole alifatyczne, takie jak metanol lub etanol, lub acetonitryl. Korzystnym mieszającym się z wodą polarnym rozpuszczalnikiem organicznym jest acetonitryl.Suitable water-miscible polar organic solvents are, for example, lower aliphatic alcohols, such as methanol or ethanol, or acetonitrile. A preferred water-miscible polar organic solvent is acetonitrile.
Reagenty dogodnie rozpuszcza się przez ogrzewanie. Zasadą jest, że pod wpływem ochładzania, pożądany diastereomer (-)-a-(difluorometylo)ornityna z kwasem (-)-O,O'-di-p-toluoilo-L-winowym krystalizuje, podczas gdy diastereomer (+)-a-difluorometylornityny z kwasem (-)-O,O'-di-p-toluoilo-L-winowym pozostaje w roztworze.The reactants are conveniently dissolved by heating. As a rule, on cooling, the desired diastereomer (-) - a- (difluoromethyl) ornithine with (-) - O, O'-di-p-toluoyl-L-tartaric acid crystallizes, while the (+) - a diastereomer -difluoromethylornithine with (-) - O, O'-di-p-toluoyl-L-tartaric acid remains in solution.
Zgodnie z wynalazkiem, tak dobiera się mieszaninę woda/mieszający się z wodą polarny rozpuszczalnik organiczny, aby pożądany diastereomer (-)-a-difluorometylornityny z kwasem (-)-O,O'-di-p-toluoilo-L-winowym krystalizował łatwo i ilościowo podczas schładzania roztworu.According to the invention, the water / water-miscible polar organic solvent mixture is selected so that the desired (-) - α-difluoromethylornithine diastereomer with (-) - O, O'-di-p-toluoyl-L-tartaric acid crystallizes easily. and quantitatively while cooling the solution.
Korzystnie, wybiera się mieszaninę acetonitryl/woda w stosunku od 0,9:1 do 1,3:1 do przeprowadzenia krystalizacji 1:1 diastereomeru (-)-a-(difluorometylo)ornityny z kwasem (-)-O,O'-di-p-toluoilo-L-winowym.Preferably, an acetonitrile / water mixture in a ratio of 0.9: 1 to 1.3: 1 is selected to effect a 1: 1 crystallization of the (-) - α- (difluoromethyl) ornithine diastereomer with the acid (-) - O, O'- di-p-toluoyl-L-tartaric.
Uwolnienie jednowodzianu jednochlorowodorku (-)-a-(difluorometylo)ornityny z diastereomeru prowadzi się poprzez zakwaszenie za pomocą kwasu mineralnego takiego, jak przykładowo, kwas solny. Stosując ekstrakcję odpowiednim rozpuszczalnikiem, otrzymuje się z wysoką wydajnością jednowodzian jednochlorowodorku (-)-a-(difluorometylo)ornityny o wysokiej czystości optycznej. Podobnie, można odzyskiwać kwas (-)-O,O'-di-p-toluoilo-L-winowy z tej ekstrakcji.The release of (-) -? - (difluoromethyl) ornithine monohydrochloride monohydrate from the diastereomer is achieved by acidification with a mineral acid such as, for example, hydrochloric acid. By means of extraction with a suitable solvent, (-) -? - (difluoromethyl) ornithine monohydrochloride monohydrate of high optical purity is obtained in high yield. Likewise, (-) - O, O'-di-p-toluoyl-L-tartaric acid can be recovered from this extraction.
Podobnie, uwolnić można diastereomer (+)-a-(difluorometylo)ornityny z kwasem (-)-di-O,O'-p-toluoilo-L-winowym, który co do zasady pozostaje w roztworze, przykładowo na drodze odparowania roztworu, jako jednowodzian jednochlorowodorku (+)-a-(difluorometylo)ornityny, który może być następnie odzyskany na drodze ekstrakcji, przez zakwaszenie kwasem mineralnym.Likewise, the (+) - α- (difluoromethyl) ornithine diastereomer can be liberated with (-) - di-O, O'-p-toluoyl-L-tartaric acid, which essentially remains in solution, for example by evaporation of the solution. as (+) - α- (difluoromethyl) ornithine monohydrate monohydrate, which can then be recovered by extraction by acidification with mineral acid.
PL 195 164 B1PL 195 164 B1
Przykłady P r zykła d IExamples P ricycles I
Wytwarzanie (-)-a-(difluorometylo)ornityny · HCl · H2OPreparation of (-) - a- (difluoromethyl) ornithine · HCl · H 2 O
9,1 g (±)-a-(difluorometylo)ornityny i 19,7 g kwasu (-)-O,O'-di-p-toluoilo-L-winowego wprowadzono do mieszaniny 150 ml acetonitrylu i 110 ml wody i ogrzewano do wrzenia, otrzymując klarowny roztwór. Podczas ochładzania, diastereomeryczna sól 1:1 (-)-a-(difluorometylo)ornityny i kwasu (-)-O,O'-di-p-toluoilo-L-winowego wykrystalizowała w temperaturze 47°C do 48°C. Krystalizację zakończono całkowicie przez ochłodzenie do temperatury 5°C do 0°C. Wykrystalizowaną sól odsączono i wysuszono. Otrzymano 9,7 g białego krystalicznego produktu.9.1 g of (±) - - (difluoromethyl) ornithine and 19.7 g of (-) - O, O'-di-p-toluoyl-L-tartaric acid were introduced into a mixture of 150 ml of acetonitrile and 110 ml of water and heated to boiling, giving a clear solution. On cooling, the 1: 1 diastereomeric salt of (-) - α- (difluoromethyl) ornithine and (-) - O, O'-di-p-toluoyl-L-tartaric acid crystallized at 47 ° C to 48 ° C. Crystallization was complete by cooling to 5 ° C to 0 ° C. The crystallized salt was filtered off and dried. 9.7 g of a white crystalline product are obtained.
[α]2°0 = -99,1° (c = 1 w MeOH).[α] 2 ° 0 = -99.1 ° (c = 1 in MeOH).
1H-NMR (400 MH^ DMSO-d6 ) δ = 7,83 (d, J = 7,7 Hz, 4H) 1 H - NMR (400 MH + DMSO - d 6) δ = 7, 83 (d, J = 7, 7 Hz, 4H)
7,30 (d, J = 7,7 Hz, 4H)7.30 (d, J = 7.7Hz, 4H)
6,21 (t, J = 54 Hz, 1H)6.21 (t, J = 54Hz, 1H)
5,63 (s, 2H)5.63 (s, 2H)
2,77 - 2,66 (m, 2H)2.77 - 2.66 (m, 2H)
2,36 (s, 6H)2.36 (s, 6H)
1,87- 1,46 (m, 4H) temperatura topnienia: 172,9 - 173,7°C.1.87-1.46 (m, 4H) mp: 172.9-173.7 ° C.
8,5 g powyższej soli wprowadzono do 100 ml wody i zadano roztworem 1,7 g stężonego kwasu solnego (o stężeniu 32,2%) w 20 ml wody. Zawiesinę poddano ekstrakcji 200 ml chloroformu. Fazę wodną odparowano do sucha. Po wysuszeniu w 40°C w piecu próżniowym pod obniżonym ciśnieniem przez noc otrzymano 3,2 g białego produktu.8.5 g of the above salt was introduced into 100 ml of water and treated with a solution of 1.7 g of concentrated hydrochloric acid (32.2% concentration) in 20 ml of water. The suspension was extracted with 200 ml of chloroform. The aqueous phase was evaporated to dryness. After drying at 40 ° C in a vacuum oven under reduced pressure overnight, 3.2 g of a white product are obtained.
[α]2°0 = -8,8° (c = 0,7 w MeOH).[α] 2 ° 0 = -8.8 ° (c = 0.7 in MeOH).
P r z y k ł a d IIP r z x l a d II
Wytwarzanie (+)-a-(difluorometylo)ornityny · HCl · H2OPreparation of (+) - a- (difluoromethyl) ornithine · HCl · H 2 O
Z odparowanego roztworu macierzystego po rozdziale przeprowadzonym jak w przykładzie l, według sposobu opisanego powyżej wydzielono jednowodzian jednochlorowodorku (+)-a-(difluorometylo)omityny o skręcalnosci optycznej [α] D = +3,1° (c = 7,0 w MeOH).The (+) - a- (difluoromethyl) omithin monohydrate monohydrate with optical rotation [α] D = + 3.1 ° (c = 7.0 in MeOH) was isolated from the evaporated mother liquor after separation as in Example 1, according to the method described above. ).
1H-NMR (400 MH^ D2O) δ = 6,30 (t, J = 54 Hz , 1H) 1 H-NMR ( 400 MH ^ D 2 O) δ = 6.30 (t, J = 54 Hz, 1H)
3,01 (m, 2H)3.01 (m, 2H)
2,05 (m, 1H)2.05 (m, 1H)
1,89 (m, 1H)1.89 (m, 1H)
1,85 (m, 1H)1.85 (m, 1H)
1,62 (m, 1H) temperatura topnienia > 240°C.1.62 (m, 1H) mp> 240 ° C.
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98117982 | 1998-09-23 | ||
| PCT/EP1999/007060 WO2000017153A1 (en) | 1998-09-23 | 1999-09-22 | METHOD FOR PRODUCING (-)-α-(DIFLUOROMETHYL)ORNITHINE-MONOHYDROCHLORIDE MONOHYDRATE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL346900A1 PL346900A1 (en) | 2002-03-11 |
| PL195164B1 true PL195164B1 (en) | 2007-08-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL99346900A PL195164B1 (en) | 1998-09-23 | 1999-09-22 | Diastereomer salts of (±)-alpha-(difluoromethyl)ornithine-monohydrochloride monohydrate and method of separation of (+)- alpha-(difluoromethyl)ornithine |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US6462229B1 (en) |
| EP (1) | EP1115696A1 (en) |
| JP (1) | JP2002526468A (en) |
| KR (1) | KR20010079913A (en) |
| CN (1) | CN1319085A (en) |
| AU (1) | AU764154B2 (en) |
| BR (1) | BR9914034A (en) |
| CA (1) | CA2345112A1 (en) |
| CZ (1) | CZ20011043A3 (en) |
| HU (1) | HUP0103658A3 (en) |
| IL (1) | IL142218A0 (en) |
| MX (1) | MXPA01003032A (en) |
| NO (1) | NO20011480L (en) |
| PL (1) | PL195164B1 (en) |
| SK (1) | SK4092001A3 (en) |
| WO (1) | WO2000017153A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7358384B2 (en) * | 2003-01-16 | 2008-04-15 | Toray Fine Chemicals Co., Ltd. | Processes for the recovery of optically active diacyltartaric acids |
| WO2005021502A1 (en) * | 2003-08-29 | 2005-03-10 | Takeda Pharmaceutical Company Limited | METHOD FOR PRODUCING OPTICALLY ACTIVE THREO-β-ALKYLTRYPTOPHAN DERIVATIVE AND INTERMEDIATE THEREOF |
| TW201617326A (en) * | 2014-03-06 | 2016-05-16 | Ａｌｐｈｏｒａ研發股份有限公司 | Crystalline derivatives of (S)-1-((2R,3R,4S,5S)-5-allyl-3-methoxy-4-(tosylmethyl)tetrahydrofuran-2-yl)-3-aminopropan-2-ol |
| JP2018507910A (en) * | 2015-02-12 | 2018-03-22 | ジ・アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・ジ・ユニバーシティ・オブ・アリゾナ | How to treat neuroblastoma |
| CN105660637B (en) * | 2016-01-07 | 2018-04-24 | 南京中医药大学 | Prevent the medicine and its application of Angelica sinensis morning a kind of sedge |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4309442A (en) * | 1977-07-11 | 1982-01-05 | Merrell Toraude Et Compagnie | Method for controlling fertility in mammals |
| US4414141A (en) | 1980-11-21 | 1983-11-08 | The Lummus Company | Hydrotreating catalyst |
| US4931557A (en) * | 1988-10-17 | 1990-06-05 | Eli Lilly And Company | Method of resolving cis 3-amino-4-(2-furyl)vinyl)-1-methoxycarbonylmethyl-azetidin-2-one and di-p-toluoyl-tartaric acid salts thereof |
| EP0871441B1 (en) * | 1996-10-04 | 2003-08-13 | Ilex Oncology, Inc. | Dfmo and taxol for the treatment or prevention of breast cancer |
| WO1998025603A1 (en) * | 1996-12-13 | 1998-06-18 | Ilex Oncology, Inc. | Isomeric pharmaceutical formulation containing dfmo for the treatment of cancer |
-
1999
- 1999-09-22 CZ CZ20011043A patent/CZ20011043A3/en unknown
- 1999-09-22 IL IL14221899A patent/IL142218A0/en unknown
- 1999-09-22 EP EP99947408A patent/EP1115696A1/en not_active Withdrawn
- 1999-09-22 BR BR9914034-9A patent/BR9914034A/en not_active IP Right Cessation
- 1999-09-22 US US09/787,420 patent/US6462229B1/en not_active Expired - Fee Related
- 1999-09-22 WO PCT/EP1999/007060 patent/WO2000017153A1/en not_active Application Discontinuation
- 1999-09-22 HU HU0103658A patent/HUP0103658A3/en unknown
- 1999-09-22 CN CN99811257A patent/CN1319085A/en active Pending
- 1999-09-22 PL PL99346900A patent/PL195164B1/en not_active IP Right Cessation
- 1999-09-22 JP JP2000574063A patent/JP2002526468A/en active Pending
- 1999-09-22 CA CA002345112A patent/CA2345112A1/en not_active Abandoned
- 1999-09-22 SK SK409-2001A patent/SK4092001A3/en unknown
- 1999-09-22 AU AU60865/99A patent/AU764154B2/en not_active Ceased
- 1999-09-22 KR KR1020017003766A patent/KR20010079913A/en not_active Application Discontinuation
- 1999-09-22 MX MXPA01003032A patent/MXPA01003032A/en not_active Application Discontinuation
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2001
- 2001-03-22 NO NO20011480A patent/NO20011480L/en not_active Application Discontinuation
Also Published As
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|---|---|
| CA2345112A1 (en) | 2000-03-30 |
| HUP0103658A3 (en) | 2003-03-28 |
| HU0103658D0 (en) | 2002-02-28 |
| CN1319085A (en) | 2001-10-24 |
| JP2002526468A (en) | 2002-08-20 |
| EP1115696A1 (en) | 2001-07-18 |
| NO20011480L (en) | 2001-03-23 |
| CZ20011043A3 (en) | 2001-09-12 |
| IL142218A0 (en) | 2002-03-10 |
| AU764154B2 (en) | 2003-08-14 |
| BR9914034A (en) | 2001-08-14 |
| NO20011480D0 (en) | 2001-03-22 |
| US6462229B1 (en) | 2002-10-08 |
| HUP0103658A2 (en) | 2002-12-28 |
| MXPA01003032A (en) | 2002-07-02 |
| PL346900A1 (en) | 2002-03-11 |
| WO2000017153A1 (en) | 2000-03-30 |
| AU6086599A (en) | 2000-04-10 |
| SK4092001A3 (en) | 2002-06-04 |
| KR20010079913A (en) | 2001-08-22 |
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| LAPS | Decisions on the lapse of the protection rights |
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